Mutational status of VHL gene and its clinical importance in renal clear cell carcinoma

Abstract

The most common subtype of renal cell carcinoma is the clear cell type (ccRCC), accounting for 75 % of cases. Inactivation of VHL gene is thought to be an early event in ccRCC carcinogenesis. Our intention was to assess whether VHL mutational status might provide useful predictive or prognostic information in patients with ccRCC. VHL messenger RNA (mRNA) expression was analyzed by in situ hybridization and its protein by immunohistochemistry on a tissue microarray containing samples from 148 cases. This was validated by qRT-PCR on 62 cases, for which RNA was available. The mutation status was assessed in 91 cases by Sanger sequencing. VHL was found mutated in 57 % of cases, with missense mutations in 26 %, nonsense in 5 %, splice site in 13 %, deletions in 39 %, indels in 8 %, duplications in 8 %, and insertions in 2 % of the cases. The prevalence of mutations by exon was the following: exon 1, 47 %; exon 2, 27 %; and exon 3, 13 %. VHL protein was expressed in a high number of cases (80 %), but significant correlations were not found between protein expression, clinical data, and survival. Importantly, of the 91 samples evaluated by sequencing, 45 were mutated, and 87 % of those were strongly positive. We found 32 novel mutations in the VHL gene in ccRCC. The presence of mutations was not concordant with mRNA or protein expression. Nonsense mutations of the VHL gene appear to be related with poorer prognosis and survival.

Development and validation of a hypoxia‑related prognostic signature for breast cancer

“…By contrast, the expression level of BTG1 in breast cancer cells has been shown to be markedly lower compared with that in normal breast cells ( 34 ). VHL has been confirmed in a number of studies as a prognostic gene for clear cell carcinoma of the kidneys, due to its potential ability to degrade HIF-1α ( 35 , 36 ). As a target gene of miRNA-155 in triple-negative breast cancer, VHL is involved in tumor angiogenesis and is associated with a poor prognosis ( 37 ).…”

HER-2 and EGFR mRNA Expression and Its Relationship with Versican in Malignant Matrix-Producing Tumors of the Canine Mammary Gland

“…RNA in situ hybridization method was performed as previously described with minor modifications [ 28 ]. The RNAscope (Advanced Cell Diagnostics, Inc., Hayward, California) approach was used in archival formalin-fixed, paraffin-embedded (FFPE) tissue to view EGFR and HER-2 mRNA in individual cells through a probe design strategy and hybridization-based on a signal amplification system to amplify signals and suppress background ( EGFR : the reference sequence, XM_533073.4 ; probe region, 725–1660; HER-2 : the reference sequence, NM_001003217.1 ; probe region, 1585–2823).…”

Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance

“…Such mutations may not, partly or fully affect interacting functions of pVHL [ 23 ], which subsequently influence differently biological pathways involved in tumor carcinogenesis [ 24 – 31 ]. Evidence of mutant VHL expression at the RNA level [ 32 , 33 ] as well as at the protein level [ 34 , 35 ] was described in other studies. Although pVHL mutant forms tend to rapidly degrade, they still may exhibit partial function [ 31 ].…”